Alcohol is one of the most commonly abused drugs in the US, with 10% of the population affected by alcohol dependence at some point in their lives. There is a critical need for the development of new medications to help alcohol dependent patients reduce their alcohol use and promote abstinence. One of key predictors of relapse is severity of alcohol craving and urge to drink, which are thought to be due to classically conditioned states, and neuroadaptive changes associated with chronic alcohol consumption and abstinence. Potential targets for new medications include gamma-aminobutyric acid (GABA), glutamate, and opioid systems, which become dysregulated with chronic excessive alcohol consumption. In the current proposal, we will evaluate a kappa-opioid receptor antagonist, benzodiazepine-GABAA alpha1 receptor antagonists/partial agonists and modulators of metabotropic glutamate receptors, as potential AUD medications to reduce persistent alcohol seeking and compulsive drinking. The proposed studies will utilize a validated drinking procedure in baboons that combines classical and operant conditioning and models characteristic patterns of human problem drinking ('too much, too fast, too often'). The procedure consists of a sequence of separate behavioral contingencies, each of which is correlated with a unique cue, to form different links of a chain of responses that ultimately resul in alcohol reinforcement. This procedure allows examination of the relationships between alcohol seeking and self-administration responses during ongoing alcohol consumption, as well as the ability to study persistence cue-maintained behaviors during abstinence. We propose to examine test drug effects on alcohol-maintained behaviors under conditions of abstinence and alcohol availability, and different dosing regimens common to AUD treatment. Aim 1 will determine whether test drugs selectively reduce alcohol seeking and alter patterns of self-administration during daily access to alcohol. Aim 2 will determine whether test drugs facilitate extinction of alcohol-directed responding during ongoing alcohol access and during abstinence. Aim 3 will determine whether initiation and maintenance of subchronic treatment with test drugs during abstinence selectively reduces seeking and intake upon return to alcohol access. Aim 4 will determine incidence of side effects of test drugs administered under conditions of ongoing drinking and abstinence. Integration of the data from these aims will be used to determine the therapeutic potential of each drug. That is, a drug with therapeutic potential would reduce cue-maintained alcohol seeking during abstinence, reduce seeking and self-administration during ongoing alcohol access, and produce few side effects. Comparison of dose effect functions in the alcohol and control groups will provide a therapeutic index of each test drug under conditions of alcohol access and abstinence. These studies will provide important, new information on the differential behavioral efficacy of compounds that target receptor mechanisms relevant to compulsive alcohol use and relapse in humans.